This project aims to further understand the adverse consequences of hypercortisolemia by investigatingpro- inflammatory markers, the GH/IGF-1 axis, and gastrointestinal appetite hormones in patients with chronic glucocorticoid excess. For this, we plan to follow patients with Cushing's Disease, due to an ACTH-secreting pituitary tumor, over time before and after surgical treatment. The specific aims of the research proposal are to: 1) determine whether patients with Cushing's Disease have elevated serum pro-inflammatorymarkers compared to obese BMI- matched and lean controls; 2) follow GH/IGF-1 deficient Cushing's patients to determine if GH/IGF-1 deficiency confers increased risk for the metabolic syndrome and visceral adiposity in cured patients; 3) characterize appetite and fasting and post-meal total and active ghrelin and PYY to determine their role in the increased appetite and abnormal body composition of glucocorticoid excess; and 4) quantify body composition, particularly adipose tissue distribution, by whole-body MRI, with respect to the adipokines leptin and adiponectin. Given our unique access to a large population of patients with pituitary Cushing's Disease, we have the ability to investigate these novel chronic effects of hypercortisolemia. In doing so, we hope to yield important new information on the metabolic and body composition abnormalities resulting from excess glucocorticoid exposure, and the pathogenesis of visceral adiposity in general. The primary overall objective of this career development award application is to provide support that will enable me to gain new research skills and experience in a mentored environment, and ultimately allow me to develop into a successful independent researcher in the areas of neuroendocrinology and pituitary diseases. My current environment is ideally suited to achieve this goal. Through Dr. Post, I have access to a large cohort of Cushing's Disease patients. My two mentors, Dr. Pamela Freda and Dr. Derek LeRoith, are highly qualified and experienced researchers in the areas of pituitary disease/acromegaly and IGF-1/obesity, respectively, and are committed to providing me with the support I need to pursue my research plans and to develop into an independent investigator. RELEVANCE (See instructions): The current widespread use of glucocorticoids results in a high prevalence of iatrogenic Cushing's Syndrome, which is associated with profound body composition changes, the metabolic syndrome, and increased cardiovascular risk. The studies outlined in this proposal aim to investigate the poorly understood mechanisms by which hypercortisolemia causes these metabolic and phenotypic changes.